tbuckley/cabot-search huggingface dataset:
Molecular Mechanisms of <i>ARID5B-</i>Mediated Genetic Susceptibility to Acute Lymphoblastic Leukemia
Authors: Xujie Zhao, Maoxiang Qian, Charnise Goodings, Yang Zhang, Wenjian Yang, Ping Wang, Beisi Xu, Cheng Tian, Ching-Hon Pui, Stephen P Hunger, Elizabeth A Raetz, Meenakshi Devidas, Mary V Relling, Mignon L Loh, Daniel Savic, Chunliang Li, Jun J Yang
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-cell ALL leukemogenesis remain largely unknown. Methods We performed targeted sequencing of ARID5B in germline DNA of 5008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3644 patients from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using dCas9-KRAB–mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided. Results We identified 54 common variants in ARID5B statistically significantly associated with leukemia risk, all of which were noncoding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P = 5.57 × 10–45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n = 349 861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P = 8.6 × 10–22 and 2.1 × 10–18, respectively). Conclusions Our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.
Patterns of recurrence and prognosis in pathologic stage I and II Merkel cell carcinoma: A multicenter, retrospective cohort analysis
Authors: Andrew D Tieniber, Adrienne B Shannon, Michael J Carr, James Sun, Karenia Landa, Kirsten M Baecher, Kevin Lynch, Harrison G Bartels, Robyn Panchaud, Michael C Lowe, Craig L Slingluff, Mark J Jameson, Kenneth Y Tsai, Mark B Faries, Georgia M Beasley, Vernon K Sondak, Giorgos C Karakousis, Jonathan S Zager, John T Miura
Journal: Journal of the American Academy of Dermatology (2022)
From small beginnings: to build an anti-eugenic future
Authors: Benedict Ipgrave, Miroslava Chavez-Garcia, Marcy Darnovsky, Subhadra Das, Charlene Galarneau, Rosemarie Garland-Thomson, Nora Ellen Groce, Tony Platt, Milton Reynolds, Marius Turda, Robert A Wilson
Journal: The Lancet (2022)
Experiments make a good breakfast, but a poor supper
Authors: Jolanda Jetten, Hema Preya Selvanathan, Charlie R. Crimston, Sarah V. Bentley, S. Alexander Haslam
Journal: Behavioral and Brain Sciences (2022)

Abstract Cesario's analysis has three key flaws. First, the focus on whether an effect is “real” (an “effects flaw”) overlooks the importance of theory testing. Second, obsession with effects (a “fetishization flaw”) sidelines theoretically informed questions about when and why an effect may arise. Third, failure to take stock of cultural and historical context (a “decontextualization flaw”) strips findings of meaning.
Missing context from experimental studies amplifies, rather than negates, racial bias in the real world
Authors: Leland Jasperse, Benjamin S. Stillerman, David M. Amodio
Journal: Behavioral and Brain Sciences (2022)

We agree with Cesario's premise but reject his conclusion: Although experimental studies of racial stereotyping, weapons perception, and shoot decisions typically exclude real-world contextual factors and thus have limited relevance to race disparities (e.g., in policing), these excluded factors comprise systemic, institutional, and individual-level biases that are more likely to amplify racial disparities than negate them.
Arterial myeloperoxidase in the detection and treatment of vulnerable atherosclerotic plaque: a new dawn for an old light
Authors: James Nadel, Andrew Jabbour, Roland Stocker
Journal: Cardiovascular Research (2022)

Abstract Intracellular myeloperoxidase (MPO) plays a specific role in the innate immune response; however, upon release into the extracellular space in the setting of inflammation, drives oxidative tissue injury. Extracellular MPO has recently been shown to be abundant in unstable atheroma and causally linked to plaque destabilization, erosion, and rupture, identifying it as a potential target for the surveillance and treatment of vulnerable atherosclerosis. Through the compartmentalization of MPO’s protective and deleterious effects, extracellular MPO can be selectively detected using non-invasive molecular imaging and targeted by burgeoning pharmacotherapies. Given its causal relationship to plaque destabilization coupled with an ability to preserve its beneficial properties, MPO is potentially a superior translational inflammatory target compared with other immunomodulatory therapies and imaging biomarkers utilized to date. This review explores the role of MPO in plaque destabilization and provides insights into how it can be harnessed in the management of patients with vulnerable atherosclerotic plaque.
A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease
Authors: Julia Z. Xu, Anna Conrey, Ingrid Frey, Eveline Gwaabe, Laurel A. Menapace, Laxminath Tumburu, Maureen Lundt, Timothy Lequang, Quan Li, Kristen Glass, Emily B. Dunkelberger, Varsha Iyer, Heidi Mangus, Charles Kung, Lenny Dang, Penelope A. Kosinski, Peter Hawkins, Neal Jeffries, William A. Eaton, Swee Lay Thein
Journal: Blood (2022)
The Course of General Cognitive Ability in Individuals With Psychotic Disorders
Authors: Katherine Jonas, Wenxuan Lian, Jennifer Callahan, Camilo J. Ruggero, Sean Clouston, Avraham Reichenberg, Gabrielle A. Carlson, Evelyn J. Bromet, Roman Kotov
Journal: JAMA Psychiatry (2022)

<h3>Importance</h3> Schizophrenia is associated with major cognitive deficits and has been conceptualized as both a neurodevelopmental and a neurodegenerative disorder. However, when deficits develop and how they change over the course of illness is uncertain. <h3>Objective</h3> To trace cognition from elementary school to old age to test neurodevelopmental and neurodegenerative theories of psychotic disorders. <h3>Design, Setting, and Participants</h3> Data were taken from the Suffolk County Mental Health Project, a first-admission longitudinal cohort study of individuals with psychotic disorders. Participants were recruited from all 12 inpatient psychiatric facilities in Suffolk County, New York. This analysis concerns the 428 participants with at least 2 estimates of general cognitive ability. Data were collected between September 1989 and October 2019, and data were analyzed from January 2020 to October 2021. <h3>Exposures</h3> Psychiatric hospitalization for psychosis. <h3>Main Outcomes and Measures</h3> Preadmission cognitive scores were extracted from school and medical records. Postonset cognitive scores were based on neuropsychological testing at 6-month, 24-month, 20-year, and 25-year follow-ups. <h3>Results</h3> Of the 428 included individuals (212 with schizophrenia and 216 with other psychotic disorders), 254 (59.6%) were male, and the mean (SD) age at psychosis onset was 27 (9) years. Three phases of cognitive change were observed: normative, declining, and deteriorating. In the first phase, cognition was stable. Fourteen years before psychosis onset, those with schizophrenia began to experience cognitive decline at a rate of 0.35 intelligence quotient (IQ) points per year (95% CI, 0.29-0.42;<i>P</i> &lt; .001), a significantly faster decline than those with other psychotic disorders (0.15 IQ points per year; 95% CI, 0.08-0.22,<i>P</i> &lt; .001). At 22 years after onset, both groups declined at a rate of 0.59 IQ points per year (95% CI, 0.25-0.94;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In this cohort study, cognitive trajectories in schizophrenia were consistent with both a neurodevelopmental and neurodegenerative pattern, resulting in a loss of 16 IQ points over the period of observation. Cognitive decline began long prior to psychosis onset, suggesting the window for primary prevention is earlier than previously thought. A window for secondary prevention emerges in the third decade of illness, when cognitive declines accelerate in individuals with schizophrenia and other psychotic disorders.
Limited surgery and conformal photon radiation therapy for pediatric craniopharyngioma: long-term results from the RT1 protocol
Authors: Drucilla Y Edmonston, Shengjie Wu, Yimei Li, Raja B Khan, Frederick A Boop, Thomas E Merchant
Journal: Neuro-Oncology (2022)

Abstract Background Our aim was to estimate long-term disease control and complications after conformal radiation therapy (CRT) in children and adolescents with craniopharyngioma. Materials and Methods Pediatric patients with craniopharyngioma (n = 101) were enrolled on or treated according to a phase II single institutional protocol from 1998. Surgery was individualized, and CRT (54Gy) was administered using a 1.0 cm or 0.5 cm clinical target volume margin. Patients were followed for 10 years by serial MR imaging and MR angiography and a battery of tests to measure the effects of treatment. Results Twenty patients had tumor progression. Twelve patients who had tumor progression died due to tumor (n = 6) or complications related to tumor or treatment (n = 6). With a median follow-up of 14.94 years for survivors, the 10 year estimates (±SE) of progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) were 78.84% ± 4.10%, 77.12% ± 4.19%, and 96.02% ± 1.95%, respectively. OS, EFS, and PFS were significantly associated with race, shunt status, and tumor volume. The 10 year cumulative incidence (±SE) of the secondary tumor (1.99% ± 1.40%), secondary malignant tumor (1.0% ± 1.0%), necrosis (1.98% ± 1.39%), vasculopathy (8.47% ± 2.90%), and permanent neurologic deficits (8.28% ± 3.37%) were estimated by competing risk analysis. Three patients required revascularization surgery. Salvage therapy was successful in 13 patients using surgery and radiosurgery. Conclusions Limited surgery and CRT using photons results in excellent tumor control. Tumor control and the incidence and severity of complications are associated with host, tumor, and treatment factors.
STING agonist-containing microparticles improve seasonal influenza vaccine efficacy and durability in ferrets over standard adjuvant
Authors: Matthew D. Gallovic, Robert D. Junkins, Adam M. Sandor, Erik S. Pena, Christopher J. Sample, Ariel K. Mason, Leslee C. Arwood, Rebecca A. Sahm, Eric M. Bachelder, Kristy M. Ainslie, Gregory D. Sempowski, Jenny P.-Y. Ting
Journal: Journal of Controlled Release (2022)
Progress toward Pig-to-Human Xenotransplantation
Authors: Richard N Pierson
Journal: New England Journal of Medicine (2022)

Interview with Dr. Richard Pierson on the implications of recent efforts to transplant pig organs into humans. (09:21)Download In light of the recent clinical cases of pig-to-human kidney and heart transplantation, taking stock of progress in xenotransplantation can help us set realistic expectations for clinical adoption of this promising technology.
Modeling zero inflation is not necessary for spatial transcriptomics
Authors: Peiyao Zhao, Jiaqiang Zhu, Ying Ma, Xiang Zhou
Journal: Genome biology (2022)

Spatial transcriptomics are a set of new technologies that profile gene expression on tissues with spatial localization information. With technological advances, recent spatial transcriptomics data are often in the form of sparse counts with an excessive amount of zero values.
The missing consequences: A fourth flaw of experiments
Authors: Adam Thomas Biggs
Journal: Behavioral and Brain Sciences (2022)

Abstract Decisions are affected by the potential consequences as much as any factor during the decision-making process. This prospective influence represents another flaw overlooked by most experiments that raises questions about the use of certain laboratory paradigms. Lethal force encounters are a prime example of this problem, where negative consequences of slow decisions and wrong decisions should be considered alongside behavior.
The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation
Authors: Miaomiao Han, Jingyu Ma, Suidong Ouyang, Yanyan Wang, Tingting Zheng, Peishan Lu, Zihan Zheng, Weiheng Zhao, Hongjin Li, Yun Wu, Baohua Zhang, Ran Hu, Kinya Otsu, Xinguang Liu, Ying Wan, Huabin Li, Gonghua Huang
Journal: Cellular and Molecular Immunology (2022)

Abstract Dendritic cells (DCs) play a critical role in controlling T helper 2 (Th2) cell-dependent diseases, but the signaling mechanism that triggers this function is not fully understood. We showed that p38α activity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines. p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation. Further study showed that p38α in cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis. Importantly, crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase, not the effector phase, and was conserved between mice and humans. Our results identify p38α signaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function, and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.
Gene-independent therapeutic interventions to maintain and restore light sensitivity in degenerating photoreceptors
Authors: Marta Zuzic, Johannes Striebel, Julia S. Pawlick, Kritika Sharma, Frank G. Holz, Volker Busskamp
Journal: Progress in Retinal and Eye Research (2022)

Neurodegenerative retinal diseases are a prime cause of blindness in industrialized countries. In many cases, there are no therapeutic treatments, although they are essential to improve patients' quality of life. A set of disease-causing genes, which primarily affect photoreceptors, has already been identified and is of major interest for developing gene therapies. Nevertheless, depending on the nature and the state of the disease, gene-independent strategies are needed. Various strategies to halt disease progression or maintain function of the retina are under research. These therapeutic interventions include neuroprotection, direct reprogramming of affected photoreceptors, the application of non-coding RNAs, the generation of artificial photoreceptors by optogenetics and cell replacement strategies. During recent years, major breakthroughs have been made such as the first optogenetic application to a blind patient whose visual function partially recovered by targeting retinal ganglion cells. Also, RPE cell transplantation therapies are under clinical investigation and show great promise to improve visual function in blind patients. These cells are generated from human stem cells. Similar therapies for replacing photoreceptors are extensively tested in pre-clinical models. This marks just the start of promising new cures taking advantage of developments in the areas of genetic engineering, optogenetics, and stem-cell research. In this review, we present the recent therapeutic advances of gene-independent approaches that are currently under clinical evaluation. Our main focus is on photoreceptors as these sensory cells are highly vulnerable to degenerative diseases, and are crucial for light detection.
Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial
Authors: Adrien Bouglé, Sophie Tuffet, Laura Federici, Marc Leone, Antoine Monsel, Thomas Dessalle, Julien Amour, Claire Dahyot-Fizelier, François Barbier, Charles-Edouard Luyt, Olivier Langeron, Bernard Cholley, Julien Pottecher, Tarik Hissem, Jean-Yves Lefrant, Benoit Veber, Matthieu Legrand, Alexandre Demoule, Pierre Kalfon, Jean-Michel Constantin, Alexandra Rousseau, Tabassome Simon, Arnaud Foucrier, Adrien Bouglé, Julien Amour, Thomas Dessalle, Florence Bellenfant Zegdi, Bernard Cholley, Julien Massot, Jean-Michel Constantin, Alexandre Demoule, Julien Mayaux, Vincent Dubée, Hervé Dupont, Jacques Duranteau, Laura Federici, Arnaud Foucrier, Thomas Geeraerts, Céline Guichon, Pierre Kalfon, Éric Kipnis, Sigismond Lasocki, Jean-Yves Lefrant, Matthieu Legrand, Marc Leone, Thomas Lescot, Bruno Lévy, Joël Cousson, Philippe Montravers, Sébastien Tanaka, Emmanuel Novy, Alexandre Ouattara, Jean-François Payen, Walter Picard, Pascale Poète, Julien Pottecher, Christophe Quesnel, Muriel Fartoukh, Anoine Tesniere, Mélanie Fromentin, Jean-Jacques Rouby, Qin Lu, Olivier Langeron, Pierre Squara, Eric Levesque, Nicolas Mongardon, Tabassome Simon, Laurence Berard, Marine Cachanado, Nora Soussi
Journal: Intensive Care Medicine (2022)
What can metabolites tell us about gliomas?
Authors: Oltea Sampetrean, Hideyuki Saya
Journal: Neuro-Oncology (2022)

Journal Article What can metabolites tell us about gliomas? Get access Oltea Sampetrean, Oltea Sampetrean Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan Corresponding Author: Oltea Sampetrean, MD, PhD, Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan (oltea@a6.keio.jp). https://orcid.org/0000-0001-5783-1049 Search for other works by this author on: Oxford Academic PubMed Google Scholar Hideyuki Saya Hideyuki Saya Division of Gene Regulation, Cancer Center, Fujita Health University, Toyoake, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 24, Issue 9, September 2022, Pages 1469–1470, https://doi.org/10.1093/neuonc/noac128 Published: 12 May 2022 Article history Published: 12 May 2022 Corrected and typeset: 02 June 2022
Stabilizing vaccines via drying: Quality by design considerations
Authors: Zahra Ghaemmaghamian, Reza Zarghami, Gavin Walker, Emmet O’Reilly, Ahmad Ziaee
Journal: Advanced Drug Delivery Reviews (2022)

Pandemics and epidemics are continually challenging human beings' health and imposing major stresses on the societies particularly over the last few decades, when their frequency has increased significantly. Protecting humans from multiple diseases is best achieved through vaccination. However, vaccines thermal instability has always been a hurdle in their widespread application, especially in less developed countries. Furthermore, insufficient vaccine processing capacity is also a major challenge for global vaccination programs. Continuous drying of vaccine formulations is one of the potential solutions to these challenges. This review highlights the challenges on implementing the continuous drying techniques for drying vaccines. The conventional drying methods, emerging technologies and their adaptation by biopharmaceutical industry are investigated considering the patented technologies for drying of vaccines. Moreover, the current progress in applying Quality by Design (QbD) in each of the drying techniques considering the critical quality attributes (CQAs), critical process parameters (CPPs) are comprehensively reviewed. An expert advice is presented on the required actions to be taken within the biopharmaceutical industry to move towards continuous stabilization of vaccines in the realm of QbD.
The relationship between epigenetic age and the hallmarks of aging in human cells
Authors: Sylwia Kabacik, Donna Lowe, Leonie Fransen, Martin Leonard, Siew-Lan Ang, Christopher Whiteman, Sarah Corsi, Howard Cohen, Sarah Felton, Radhika Bali, Steve Horvath, Ken Raj
Journal: Nature Aging (2022)

Abstract Epigenetic clocks are mathematically derived age estimators that are based on combinations of methylation values that change with age at specific CpGs in the genome. These clocks are widely used to measure the age of tissues and cells 1,2 . The discrepancy between epigenetic age (EpiAge), as estimated by these clocks, and chronological age is referred to as EpiAge acceleration. Epidemiological studies have linked EpiAge acceleration to a wide variety of pathologies, health states, lifestyle, mental state and environmental factors 2 , indicating that epigenetic clocks tap into critical biological processes that are involved in aging. Despite the importance of this inference, the mechanisms underpinning these clocks remained largely uncharacterized and unelucidated. Here, using primary human cells, we set out to investigate whether epigenetic aging is the manifestation of one or more of the aging hallmarks previously identified 3 . We show that although epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.
Abstract A005: Transcriptional profiling of tumor heterogeneity and chemoresistance in small cell lung cancer
Authors: Hannah Wollenzien, Yohannes Afeworki, Michael S. Kareta
Journal: Cancer Research (2022)

Abstract Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where multiple populations of phenotypically different cells exist and contribute differentially to tumor dynamics. This tumor is characterized by a very low 2- year survival rate, high metastatic rates, and rapid acquisition of chemoresistance. Beyond first-line chemotherapy, targeted treatment options are scarce, and none take in to consideration the complex genetics of the tumor. The heterogeneous nature of this tumor makes it difficult to study and to treat, as current attempts to understand tumor dynamics use a bulk approach that averages the contribution of all cells within a tumor. This work uses a cellular barcoding lineage tracing approach combined with single-cell RNA sequencing (scRNA-seq) to understand tumor heterogeneity and evolution of SCLC in both a xenograft of human SCLC cell lines and an in vivo system using a genetically modified mouse model with alterations in the same driver genes as the majority of humans with SCLC. Tumors are sampled pre-growth, post-growth and metastasis, and pre- and post- chemotherapy. By paring the barcode populations that exist in samples over time, in metastasis, or in chemoresistance, a clonal evolution map of growth, metastasis, and chemoresistance can be generated, based on shared barcodes and convergent or divergent transcriptomic profiles. In validation of scRNA-seq data, we have identified the cancer testis antigens (CTA) PAGE5 and GAGE2A as markers of chemoresistance in human SCLC. CTAs have been successfully targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC. In mouse tumors, we have identified an AP-1-high population of early tumor cells that are maintained throughout the course of the disease. The knowledge gained in this work will pave the way for the identification of new therapeutic targets for SCLC. Citation Format: Hannah Wollenzien, Yohannes Afeworki, Michael S. Kareta. Transcriptional profiling of tumor heterogeneity and chemoresistance in small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A005.